Throughout this application various publications are referenced by arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the Sequence Listing. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which the invention pertains.
The study of functional platelet disorders has traditionally consisted of a description of the abnormal responsiveness of patient platelets in a variety of experimental conditions, together with a genetic analysis of the families involved. In most cases, however, a precise correlate of abnormal functions with underlying abnormal structure has not been possible. Recently, the entire cDNA sequences encoding the protein chains comprising the platelet glycoprotein (GP) IIb/IIIa receptor (1-6) and the platelet GPIb/IX receptor (7-10) have been obtained, opening the possibility for study of the molecular basis of disorders affecting these receptors.
Bray and Shuman (11) first identified an abnormal gene coding for GPIIIa in one Glanzmann thrombasthenia family. A major deletion of genomic DNA coding for GPIIb (12) was subsequently described in another thrombasthenic patient. A nonsense mutation has also been reported in the GPIb.alpha. gene, leading to incomplete synthesis of the GPIb.alpha. protein in a patient with Bernard-Soulier disease (BSD) (13). A point mutation in the GPIb.alpha. gene coding for a valine in place of the wild-type glycine in the GPIb.alpha. of patients with platelet-type von Willebrand disease has also recently been identified and is disclosed in copending, coassigned U.S. Ser. No. 770,968, filed Oct. 7, 1991, of which the subject application is a continuation-in-part.
Absence of the GPIb/IX receptor for von Willebrand factor (vWF) is the hallmark of the autosomal recessive bleeding disorder, BSD. Applicants have previously described in preliminary form (15) a family in whom attributes of BSD appear to be transmitted in an autosomal dominant manner, and in whom there appears to be a qualitative, rather than quantitative, abnormality of GPIb.alpha.. Descriptions of apparently qualitative abnormalities of GPIb.alpha. have also been reported in patients of Italian (16) and Norwegian (17) origin.
The subject invention provides a molecular characterization of the abnormality in the American family applicants have studied.